NCT04486625已完成1 期
AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC STUDY OF MULTIPLE INTRAVENOUS DOSES OF AZTREONAM AND AVIBACTAM IN SUBJECTS WITH SEVERE RENAL IMPAIRMENT AND NORMAL RENAL FUNCTION
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Maximum Plasma Concentration (Cmax) of ATM
研究概览
简要总结
This Phase 1 study is being conducted to evaluate the effect of severe renal impairment on the PK, safety and tolerability of Aztreonam-Avibactam. Results from this study along with previous renal impairment data from each of the Aztreonam-Avibactam components will be used to confirm the proposed dosing adjustment in severe renal impairment which was based on modelling/simulation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy female subjects and/or male subjects between the ages of 18 and 75 years, inclusive. Male and female subjects of childbearing potential must agree to use highly effective method(s) of contraception
- •Body mass index (BMI) of 17.5 to 40.5 kg/m2; and a total body weight >50 kg (110 lb)
- •Stable renal function defined as </=25% difference between 2 measurements of eGFR obtained on 2 separate occasions during the screening period that are at least 72 hours but no more than 14 days apart Specific Requirements for Healthy Subjects with Normal Renal Function
- •Normal renal function (eGFR>/= 80 mL/min) at Screening based on the Day -2 value, using the MDRD formula adjusting for BSA
- •Demographically comparable to the group of subjects with severe impaired renal function Specific Requirements for Subjects with Severe Renal Impairment
- •Good general health commensurate with the population with chronic kidney disease.
- •Documented severe renal impairment indicated by eGFR >15 -</=30 mL/min but not requiring hemodialysis, using the MDRD formula adjusting for BSA
排除标准
- •Positive urine drug test
- •History of regular alcohol use (within 6 months) exceeding 7 drinks/week for female or 14 drinks/week for male subjects
- •Treatment with an investigational product within 30 days or 5 half-lives preceding the first dose of investigational product (whichever is longer)
- •Subjects with abnormalities in clinical laboratory tests (AST, ALT, Total bilirubin, aPTT, PT, INR) at Screening
- •Pregnant females; breastfeeding females; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception
- •Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of investigational product. For subjects with severe renal impairment, concomitant medications may be given if considered necessary for the subject welfare (eg, standard therapy for underlying diseases), are not contraindicated with the study drug, and are unlikely to interfere with the PK/PD response of the study drug. Use of oral anticoagulants and potent inhibitors of OAT1 and/or OAT3 (eg, probenecid) are prohibited in all subjects.
- •Blood donation (excluding plasma donations) of approximately 1 pint or more within 60 days prior to dosing
- •History of sensitivity to heparin or heparin-induced thrombocytopenia
- •History of serious allergy, hypersensitivity or any serious reaction to aztreonam, carbapenem, monobactam or other beta-lactam antibiotics, avibactam, or any of the excipients of the respective (investigational) medicinal products
- •History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
- •Other acute or chronic medical or psychiatric condition
- •Past or current history of epilepsy or seizure disorders excluding febrile seizures of childhood Exclusion criteria: Subjects with Severe Renal Impairment
- •Any significant hepatic, cardiac, or pulmonary disease
- •Renal allograft recipients or subjects who are clinically nephrotic
- •Subjects requiring dialysis
- •Screening supine 12-lead ECG demonstrating QT interval corrected by Fridericia's formula (QTcF) >470 msec or a QRS interval >120 msec
- •Screening supine BP >/=180 millimeters of mercury (mm Hg) (systolic) or >/=110 mm Hg (diastolic), on a single measurement (confirmed by a single repeat, if necessary) following at least 5 minutes of rest Exclusion criteria: Subjects with Normal Renal Function
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including clinically relevant and significant drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing)
- •Screening supine 12-lead ECG demonstrating QTcF >450 msec or a QRS interval >120 msec
- •Screening supine BP >/=140 mm Hg (systolic) or >/=90 mm Hg (diastolic), following at least 5 minutes of supine rest
研究组 & 干预措施
Cohort 1
Experimental
Normal renal function
干预措施: Aztreonam-Avibactam (Drug)
Cohort 2
Experimental
Severe renal impairment (not on dialysis)
干预措施: Aztreonam-Avibactam (Drug)
结局指标
主要结局
Maximum Plasma Concentration (Cmax) of ATM
时间窗: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
The Cmax of ATM was observed directly from data.
Cmax of AVI
时间窗: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
The Cmax of AVI was observed directly from data.
Total Daily Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours at Steady-state (AUC0-24,ss) of Aztreonam (ATM)
时间窗: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
AUC0-24,ss of ATM in Cohort 1 was calculated by 4\*AUC0-tau (tau = 6 hours), where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). AUC0-24,ss of ATM in Cohort 2 was calculated by 3\*AUC0-tau (tau = 8 hours), where AUC0-tau was area under the plasma concentration-time profile from time 0 to time tau (the dosing interval).
AUC0-24,ss of Avibactam (AVI)
时间窗: Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.
AUC0-24,ss of AVI in Cohort 1 was calculated by 4\*AUC0-tau (tau = 6 hours), where AUC0-tau was area under the concentration-time profile from time 0 to time tau (the dosing interval). AUC0-24,ss of AVI in Cohort 2 was calculated by 3\*AUC0-tau (tau = 8 hours), where AUC0-tau was area under the plasma concentration-time profile from time 0 to time tau (the dosing interval).
次要结局
- Observed Plasma Concentration at the End of the Dosing Interval (Tau) (Ctau) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Time for Cmax (Tmax) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Terminal Elimination Half-life (t1/2) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Area Under the Plasma Concentration-time Profile From Time 0 to Time Tau (The Dosing Interval)(AUC0-tau) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Renal Clearance (CLr) of ATM(In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.)
- Apparent Volume of Distribution (Vz) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Percent of Dose Recovered Unchanged in Urine up to Time Tau (Ae0-tau%) of ATM(In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.)
- Ae0-tau of AVI(In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.)
- Number of Participants With TEAEs (Treatment-related)(Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days).)
- Clearance (CL) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- AUC0-tau of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Ctau of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Apparent Volume of Distribution at Steady-state (Vss) of ATM(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Tmax of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) (All-causality)(Day 1 up to at least 28 days after last dose of study medication (maximum of 33 days).)
- Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)(Days 1 to 3)
- Cumulative Amount of Drug Recovered Unchanged in Urine up to Time Tau (Ae0-tau) of ATM(In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.)
- t1/2 of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Vss of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- CL of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- CLr of AVI(In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.)
- Vz of AVI(Predose, 2, 3, 3.25, 3.5, 3.75, 4, 5, 6, 8, 12, 16, and 24 hours after start of a maintenance dose infusion on Day 3.)
- Ae0-tau% of AVI(In Cohort 1, at predose on Day 3, during 0-2, 2-4, and 4-6 hours after the start of a maintenance dose infusion. In Cohort 2, at predose on Day 3, during 0-2, 2-4, 4-6, and 6-8 hours after the start of a maintenance dose infusion.)
- Number of Participants With Categorical Post-Baseline Vital Signs Data(Days 1 to 3)
- Number of Participants With Abnormal Electrocardiogram (ECG)(Days 1 to 3)
研究者
研究点 (1)
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